Keywords lymphoid development, lymphocytes, Signal Transduction, gene expression, thymus Our main research interests reside in the intracellular events -changes in signaling and in gene expression- which direct T-lymphocyte differentiation and survival, both during intrathymic T-cell development and in mature T-cells. Our first experimental approach focuses on T-cell positive selection, an intrathymic process which ensures the generation of an efficient T-cell repertoire by rescuing 'useful' thymocytes from programmed cell death and by inducing their differentiation into mature T-cells. While it has been shown that T-cell Receptor (TCR) engagement on thymocytes is necessary to trigger positive selection, it has remained unclear whether attributes of TCR signals (including their strength or duration) also dictate subsequent differentiation or survival events required for complete intrathymic maturation. To address these issues, we have generated a recombinant mouse model in which expression of Zap70, a tyrosine kinase required for TCR signal transduction, decreases in thymocytes that have been signaled to undergo positive selection. Thus, thymocytes in such mice can only receive transient, but not persistent, TCR signals. Using this model, we have shown that interruption of intrathymic TCR signaling in vivo (i) prevents thymocytes from completing their intrathymic maturation, despite the fact that they undergo initial differentiation events that characterize positive selection and (ii) precludes the differentiation of CD4-lineage T-cells. By breeding these mice with mouse lines carrying defined genetic modifications, we are currently investigating the intracellular signaling pathways which transduce differentiation and survival signals during intrathymic selection. As a second approach, we are developing conditional versions of intracellular signaling molecules that can be turned 'on' or 'off' by small-size ligands, to interfere with T-cell signal transduction in vivo and to monitor signaling and gene expression during the course of an immune response or during intrathymic development.